Manufacture of Pharmaceutical Compositions

ABSTRACT

The present invention relates to particles and to methods of making particles. In particular, the invention relates to methods of making composite active particles comprising a pharmaceutically active material for pulmonary inhalation, the method comprising a jet milling process.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/337,596 filed Dec. 27, 2011, which is a continuation of U.S.application Ser. No. 10/571,146 filed Jul. 17, 2006, now patented asU.S. Pat. No. 8,182,838 which issued May 22, 2012, which is a UnitedStates national stage of International Application No.PCT/GB2004/003996, filed Sep. 15, 2004, which was published asInternational Publication No. WO 2005/025536, and which claims benefitof United Kingdom Application No. 0321607.4 filed, Sep. 15, 2003, theentire contents of which are hereby expressly incorporated herein byreference thereto.

The present invention relates to particles and to methods of makingparticles. In particular, the invention relates to methods of makingcomposite particles comprising a pharmaceutically active material and anadditive material, for pulmonary inhalation, the methods comprising aco-jet milling process.

The lung provides an obvious target for local administration offormulations which are intended to cure or alleviate respiratory orpulmonary diseases, such as cystic fibrosis (CF), asthma, lung cancer,etc. The lung also provides a route for delivery of systemically actingformulations to the blood stream, for example, for delivery of activeagents which are not suitable for oral ingestion, such as agents thatdegrade in the digestive tract before they can be absorbed, and thoserequiring an extremely rapid onset of their therapeutic action.

It is known to administer pharmaceutically active agents to a patient inthe form of fine, dry particles (active particles), for example, bypulmonary administration of a particulate medicament composition whichis inhaled by the patient. Known devices for the administration of drugsto the respiratory system include pressurised metered dose inhalers(pMDIs) and dry powder inhalers (DPIs).

The size of the active particles is of great importance in determiningthe site of the absorption in the lung. In order for the particles becarried deep into the lungs, the particles must be very fine, forexample having a mass median aerodynamic diameter (MMAD) of less than 10μm. Particles having aerodynamic diameters greater than about 10 μm arelikely to impact the walls of the throat and generally do not reach thelung. Particles having aerodynamic diameters in the range of about 5 μmto about 2 μm will generally be deposited in the respiratory bronchioleswhereas smaller particles having aerodynamic diameters in the range ofabout 3 to about 0.05 μm are likely to be deposited in the alveoli andto be absorbed into the bloodstream.

Fine particles, that is those with an MMAD of less than about 10 μm tendto be increasingly thermodynamically unstable due to their high surfacearea to volume ratio, which provides an increasing surface free energywith this decreasing particle size, and consequently increases thetendency of particles to agglomerate and the strength of theagglomerate. In the inhaler, agglomeration of fine particles andadherence of such particles to the walls of the inhaler are problemsthat result in the fine particles leaving the inhaler as large, stableagglomerates, or being unable to leave the inhaler and remaining adheredto the interior of the device, or even clogging or blocking the inhaler.

The uncertainty as to the extent of formation of stable agglomerates ofthe particles between each actuation of the inhaler, and also betweendifferent inhalers and different batches of particles, leads to poordose reproducibility. Furthermore, the formation of agglomerates meansthat the MMAD of the active particles can be vastly increased, withagglomerates of the active particles not reaching the required part ofthe lung.

The metered dose (MD) of a dry powder formulation is the total mass ofactive agent present in the metered form presented by the inhaler devicein question. For example, the MD might be the mass of active agentpresent in a capsule for a Cyclohaler (trade mark), or in a foil blisterin an Aspirair (trade mark) device.

The emitted dose (ED) is the total mass of the active agent emitted fromthe device following actuation. It does not include the material leftinside or on the surfaces of the device. The ED is measured bycollecting the total emitted mass from the device in an apparatusfrequently referred to as a dose uniformity sampling apparatus (DUSA),and recovering this by a validated quantitative wet chemical assay.

The fine particle dose (FPD) is the total mass of active agent which isemitted from the device following actuation which is present in anaerodynamic particle size smaller than a defined limit

This limit is generally taken to be Si.tm if not expressly stated to bean alternative limit, such as 3 μm or 1 μm, etc. The FPD is measuredusing an impactor or impinger, such as a twin stage impinger (TSI),multi-stage liquid impinger (MSLI), Andersen Cascade Impactor (ACI) or aNext Generation Impactor (NGI). Each impactor or impinger has apre-determined aerodynamic particle size collection cut-off point foreach stage. The FPD value is obtained by interpretation of thestage-by-stage active agent recovery quantified by a validatedquantitative wet chemical assay where either a simple stage cut is usedto determine FPD or a more complex mathematical interpolation of thestage-by-stage deposition is used.

The fine particle fraction (FPF) is normally defined as the FPD dividedby the ED and expressed as a percentage. Herein, the FPF of ED isreferred to as FPF(ED) and is calculated as FPF(ED)=(FPD/ED)×100%.

The fine particle fraction (FPF) may also be defined as the FPD dividedby the MD and expressed as a percentage. Herein, the FPF of MD isreferred to as FPF(MD), and is calculated as FPF(MD)=(FPD/MD)×100%.

The terms “delivered dose” or “DD” and “emitted dose” or “ED” are usedinterchangeably herein. These are measured as set out in the current EPmonograph for inhalation products.

“Actuation of an inhaler” refers to the process during which a dose ofthe powder is removed from its rest position in the inhaler. That steptakes place after the powder has been loaded into the inhaler ready foruse.

The tendency of fine particles to agglomerate means that the FPF of agiven dose can be highly unpredictable and a variable proportion of thefine particles will be administered to the lung, or to the correct partof the lung, as a result. This is observed, for example, in formulationscomprising pure drug in fine particle form. Such formulations exhibitpoor flow properties and poor FPF.

In an attempt to improve this situation and to provide a consistent FPFand FPD, dry powder formulations often include additive material.

The additive material is intended to reduce the adhesion and cohesionexperienced by the particles in the dry powder formulation. It isthought that the additive material interferes with the weak bondingforces between the small particles, helping to keep the particlesseparated and reducing the adhesion of such particles to one another, toother particles in the formulation if present and to the internalsurfaces of the inhaler device. Where agglomerates of particles areformed, the addition of particles of additive material decreases thestability of those agglomerates so that they are more likely to break upin the turbulent air stream and collisions created on actuation of theinhaler device, whereupon the particles are expelled from the device andinhaled. As the agglomerates break up, the active particles may returnto the form of small individual particles or agglomerates of smallnumbers of particles which are capable of reaching the lower lung.

In the prior art, dry powder formulations are discussed which includedistinct particles of additive material (generally of a size comparableto that of the fine active particles). In some embodiments, the additivematerial may form a coating, generally a discontinuous coating, on theactive particles and/or on any carrier particles.

Preferably, the additive material is an anti-adherent material and itwill tend to reduce the cohesion between particles and will also preventfine particles becoming attached to the inner surfaces of the inhalerdevice. Advantageously, the additive material is an anti-friction agentor glidant and will give the powder formulation better flow propertiesin the inhaler. The additive materials used in this way may notnecessarily be usually referred to as anti-adherents or anti-frictionagents, but they will have the effect of decreasing the adhesion andcohesion between the particles or improving the flow of the powder. Theadditive materials are sometimes referred to as force control agents(FCAs) and they usually lead to better dose reproducibility and higherFPFs.

Therefore, an additive material or FCA, as used herein, is a materialwhose presence on the surface of a particle can modify the adhesive andcohesive surface forces experienced by that particle, in the presence ofother particles and in relation to the surfaces that the particles areexposed to. In general, its function is to reduce both the adhesive andcohesive forces.

The reduced tendency of the particles to bond strongly, either to eachother or to the device itself, not only reduces powder cohesion andadhesion, but can also promote better flow characteristics. This leadsto improvements in the dose reproducibility because it reduces thevariation in the amount of powder metered out for each dose and improvesthe release of the powder from the device. It also increases thelikelihood that the active material, which does leave the device, willreach the lower lung of the patient.

It is favourable for unstable agglomerates of particles to be present inthe powder when it is in the inhaler device. As indicated above, for apowder to leave an inhaler device efficiently and reproducibly, theparticles of such a powder should be large, preferably larger than about40 μm. Such a powder may be in the form of either individual particleshaving a size of about 40 μm or larger and/or agglomerates of finerparticles, the agglomerates having a size of about 40 μm or larger. Theagglomerates formed can have a size of as much as about 100 μm and, withthe addition of the additive material, those agglomerates are morelikely to be broken down efficiently in the turbulent airstream createdon inhalation. Therefore, the formation of unstable agglomerates ofparticles in the powder may be favoured compared with a powder in whichthere is substantially no agglomeration.

The reduction in the cohesion and adhesion between the active particlescan lead to equivalent performance with reduced agglomerate size, oreven with individual particles.

In a further attempt to improve extraction of the dry powder from thedispensing device and to provide a consistent FPF and FPD, dry powderformulations often include coarse carrier particles of excipientmaterial mixed with fine particles of active material. Rather thansticking to one another, the fine active particles tend to adhere to thesurfaces of the coarse carrier particles whilst in the inhaler device,but are supposed to release and become dispersed upon actuation of thedispensing device and inhalation into the respiratory tract, to give afine suspension. The carrier particles preferably have MMADs greaterthan about 60 μm.

The inclusion of coarse carrier particles is also very attractive wherevery small doses of active agent are dispensed. It is very difficult toaccurately and reproducibly dispense very small quantities of powder andsmall variations in the amount of powder dispensed will mean largevariations in the dose of active agent where the powder comprises mainlyactive particles.

Therefore, the addition of a diluent, in the form of large excipientparticles will make dosing more reproducible and accurate.

Carrier particles may be of any acceptable excipient material orcombination of materials. For example, the carrier particles may becomposed of one or more materials selected from sugar alcohols, polyolsand crystalline sugars. Other suitable carriers include inorganic saltssuch as sodium chloride and calcium carbonate, organic salts such assodium lactate and other organic compounds such as polysaccharides andoligosaccharides. Advantageously, the carrier particles comprise apolyol. In particular, the carrier particles may be particles ofcrystalline sugar, for example mannitol, dextrose or lactose.Preferably, the carrier particles are composed of lactose.

However, a further difficulty is encountered when adding coarse carrierparticles to a composition of fine active particles and that difficultyis ensuring that the fine particles detach from the surface of the largeparticles upon actuation of the delivery device.

The step of dispersing the active particles from other active particlesand from carrier particles, if present, to form an aerosol of fineactive particles for inhalation is significant in determining theproportion of the dose of active material which reaches the desired siteof absorption in the lungs. In order to improve the efficiency of thatdispersal, it is known to include in the composition additive materialsof the nature discussed above. Compositions comprising fine activeparticles and additive materials are disclosed in WO 97/03649 and WO96/23485.

It is an aim of the present invention to provide a method of producingdry powder compositions which have physical and chemical propertieswhich lead to an enhanced FPF and FPD. This will lead to greater dosingefficiency, with a greater proportion of the active agent beingdispensed and reaching the desired part of the lung for achieving therequired therapeutic effect.

It is also an aim of the present invention to provide a method ofproducing powders wherein the method achieves a further reduction in thesize of the active particles, preferably so that the particles are of anappropriate size for administration to the deep lung by inhalation.Preferably, this is possible using both active dry powder inhalerdevices and passive dry powder inhaler devices.

In particular, the present invention seeks to optimise the preparationof particles of active agent used in the dry powder composition byengineering the particles making up the dry powder composition and, inparticular, by engineering the particles of active agent. It is proposedto do this by adjusting and adapting the milling process used to formthe particles of active agent.

According to a first aspect of the present invention, a method isprovided for making composite active particles for use in apharmaceutical composition for pulmonary inhalation, the methodcomprising jet milling active particles in the presence of additivematerial, preferably wherein the jet milling is conducted using air or acompressible gas or fluid. Preferably, the additive material is a forcecontrol agent, as defined herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph presenting the life dose uniformity for formulation“6C”.

FIG. 2 is a graph presenting the life dose uniformity for formulation“12A”.

FIG. 3 shows the particle size distribution of the raw materialmicronized lactose.

FIG. 4 shows the particle size distribution of the raw materialapomorphine.

FIG. 5 shows the particle size distribution of the raw materialclobozam.

FIG. 6 shows the particle size distribution of the clobozam formulationcomprising 95% clobozam and 5% mechanofused magnesium stearate.

FIG. 7 shows the particle size distribution of the clobozam formulationcomprising 95% clobozam and 5% co-jet milled Aerocine.

FIG. 8 shows the particle size distribution of the clobozam formulationcomprising 95% clobozam and 5% co-jet milled leucine.

FIG. 9 shows the particle size distribution of the apomorphineformulation comprising 75% lactose, 20% apomorphine and 5% co-jet milledleucine.

FIG. 10 also shows the particle size distribution of the apomorphineformulation comprising 75% lactose, 20% apomorphine and 5% co-jet milledleucine.

In the conventional use of the word, “milling” means the use of anymechanical process which applies sufficient force to the particles ofactive material that it is capable of breaking coarse particles (forexample, particles with an MMAD greater than 100 μm) down to fineparticles (for example, having an MMAD not more than 50 μn). In thepresent invention, the term “milling” also refers to deagglomeration ofparticles in a formulation, with or without particle size reduction. Theparticles being milled may be large or fine prior to the milling step.

In the prior art, co-milling or co-micronising active agents andadditive materials have been suggested. It is stated that milling can beused to substantially decrease the size of particles of active agent.However, if the particles of active agent are already fine, for examplehave an MMAD of less than 20 μm prior to the milling step, the size ofthose particles may not be significantly reduced where the milling ofthese active particles takes place in the presence of an additivematerial. Rather, milling of fine active particles with additiveparticles using the methods described in the prior art (for example, inWO 02/43701) will result in the additive material becoming deformed andbeing smeared over or fused to the surfaces of the active particles. Theresultant composite active particles have been found to be less cohesiveafter the milling treatment. However, there is still the disadvantagethat this is not combined with a significant reduction in the size ofthe particles.

The prior art mentions two types of processes in the context ofco-milling or co-micronising active and additive particles.

First, there is the compressive type process, such as mechanofusion,cyclomixing and similar methods. As the name suggests, mechanofusion isa dry coating process designed to mechanically fuse a first materialonto a second material. The first material is generally smaller and/orsofter than the second. The mechanofusion and cyclomixing workingprinciples are distinct from alternative milling techniques in having aparticular interaction between an inner element and a vessel wall, andare based on providing energy by a controlled and substantialcompressive force. The term mechanofusion is used here to encompass anyprocess which operates in such a manner, and applies in a rotationalvessel a controlled and substantial compressive force. “Food processor”type mixers are not considered useful for the processes required in thepresent invention. Such mixers do not provide the necessary compressiveforces. They include conventional mixing blades and these are notarranged with a small enough gap between the blades and the vessel wall.

When fine active particles and additive particles are fed into themechanofusion driven vessel (such as a MechanoFusion system (HosokawaMicron Ltd)), they are subject to a centrifugal force and are pressedagainst the vessel inner wall. The powder is compressed between thefixed clearance of the drum wall and an inner element with high relativespeed between drum and element. The inner wall and the element togetherform a gap or nip in which the particles are pressed together. As aresult, the particles experience very high shear forces and very strongcompressive stresses as they are trapped between the inner drum wall andthe inner element. The particles are pressed against each other withenough energy to locally heat and soften, break, distort, flatten andwrap the additive particles around the core particle to form a coating.The energy is generally sufficient to break up agglomerates and somedegree of size reduction of both components may occur.

These mechanofusion and cyclomixing processes apply a high enough degreeof force to separate the individual particles of active material and tobreak up tightly bound agglomerates of the active particles such thateffective mixing and effective application of the additive material tothe surfaces of those particles is achieved. An especially desirableaspect of the described co-milling processes is that the additivematerial becomes deformed in the milling and may be smeared over orfused to the surfaces of the active particles.

However, in practice, this compression process produces little or nomilling (i.e. size reduction) of the drug particles, especially wherethey are already in a micronised form (i.e. <10 μm), the only physicalchange which may be observed is a plastic deformation of the particlesto a rounder shape.

Secondly, there are the impact milling processes involved in ballmilling and the use of a homogenizer.

Ball milling is a suitable milling method for use in the prior artco-milling processes. Centrifugal and planetary ball milling areespecially preferred methods. Alternatively, a high pressure homogenisermay be used in which a non-compressible fluid containing the particlesis forced through a valve at high pressure producing conditions of highshear and turbulence. Such homogenisers may be more suitable than ballmills for use in large scale preparations of the composite activeparticles.

Suitable homogensiers include EmulsiFlex high pressure homogeniserswhich are capable of pressures up to 4000 bar, Niro Soavi high pressurehomogenisers (capable of pressures up to 2000 bar), and MicrofluidicsMicrofluidisers (capable of pressures up to 2750 bar). The milling stepmay, alternatively, involve a high energy media mill or an agitator beadmill, for example, the Netzsch high energy media mill, or the DYNO-mill(Willy A. Bachofen AG, Switzerland).

These processes create high-energy impacts between media and particlesor between particles. In practice, while these processes are good atmaking very small particles, it has been found that neither the ballmill nor the homogenizer was effective in producing dispersionimprovements in resultant drug powders in the way observed for thecompressive process. It is believed that the second impact processes arenot as effective in producing a coating of additive material on eachparticle.

Conventional methods comprising co-milling active material with additivematerials (as described in WO 02/43701) result in composite activeparticles which are fine particles of active material with an amount ofthe additive material on their surfaces. The additive material ispreferably in the form of a coating on the surfaces of the particles ofactive material. The coating may be a discontinuous coating. Theadditive material may be in the form of particles adhering to thesurfaces of the particles of active material.

At least some of the composite active particles may be in the form ofagglomerates. However, when the composite active particles are includedin a pharmaceutical composition, the additive material promotes thedispersal of the composite active particles on administration of thatcomposition to a patient, via actuation of an inhaler.

Jet mills are capable of reducing solids to particle sizes in thelow-micron to submicron range. The grinding energy is created by gasstreams from horizontal grinding air nozzles. Particles in the fluidizedbed created by the gas streams are accelerated towards the centre of themill, colliding with slower moving particles. The gas streams and theparticles carried in them create a violent turbulence and as theparticles collide with one another they are pulverized.

In the past, jet milling has not been considered attractive forco-milling active and additive particles, processes like mechanofusionand cyclomixing or equivalent being clearly preferred. The collisionsbetween the particles in a jet mill are somewhat uncontrolled and thoseskilled in the art, therefore, considered it unlikely for this techniqueto be able to provide the desired deposition of a coating of additivematerial on the surface of the active particles. Moreover, it wasbelieved that, unlike the situation with mechanofusion, cyclomixing andsimilar processes, segregation of the powder constituents occurred injet mills, such that the finer particles, that were believed to be themost effective, could escape from the process. In contrast, it could beclearly envisaged how techniques such as mechanofusion would result inthe desired coating.

It should also be noted that it was also previously believed that thecompressive or impact milling processes must be carried out in a closedsystem, in order to prevent segregation of the different particles. Thishas also been found to be untrue and the co-jet milling processesaccording to the present invention do not need to be carried out in aclosed system. Even in an open system, the co-jet milling hassurprisingly been found not to result in the loss of the smallparticles, even when using leucine as the additive material.

It has now unexpectedly been discovered that composite particles ofactive and additive material can be produced by co-jet milling thesematerials. The resultant particles have excellent characteristics whichlead to greatly improved performance when the particles are dispensedfrom a DPI for administration by inhalation. In particular, co-jetmilling active and additive particles can lead to further significantparticle size reduction. What is more, the composite active particlesexhibit an enhanced FPD and FPF, compared to those disclosed in theprior art.

The effectiveness of the promotion of dispersal of active particles hasbeen found to be enhanced by using the co-jet milling methods accordingto the present invention in comparison to compositions which are made bysimple blending of similarly sized particles of active material withadditive material. The phrase “simple blending” means blending ormixing—using conventional tumble blenders or high shear mixing andbasically the use of traditional mixing apparatus which would beavailable to the skilled person in a standard laboratory.

It has been found that, contrary to previous belief, co-jet milling canbe used to produce sufficiently complete coatings of additive material,which have now been observed to substantially improve the dispersion ofthe powders from an inhaler. The jet milling process can also beadjusted to tailor the composite particles to the type of inhaler deviceto be used to dispense the particles. The inhaler device may be anactive inhaler device, such as Aspirair (trade mark) or it may be apassive device.

Further, the co-jet milling process may optionally also be arranged soas to significantly mill the active particles, that is, to significantlyreduce the size of the active particles: The co-jet milling of thepresent invention may even, in certain circumstances, be more efficientin the presence of the additive material than it is in the absence ofthe additive material. The benefits are that it is therefore possible toproduce smaller particles for the same mill, and it is possible toproduce milled particles with less energy. Co-jet milling should alsoreduce the problem of amorphous content by both creating less amorphousmaterial, as well as hiding it below a layer of additive material.

The impact forces of the co-jet milling are sufficient to break upagglomerates of drug, even micronised drug, and are effective atdistributing the additive material to the consequently exposed faces ofthe particles. This is an important aspect of the present invention. Ithas been shown that if the energy of the process is not sufficient tobreak up the agglomerates of drug (for example, as will be the case whenone uses a conventional blender), the additive material merely coats theagglomerates and these agglomerates can even be compressed, making themeven more difficult to disperse. This is clearly undesirable when one isseeking to prepare a dry powder for administration by inhalation.

Fine particles of active material suitable for pulmonary administrationhave often been prepared by milling in the past. However, when usingmany of the known milling techniques, once the particles reach a minimumsize, referred to as the “critical size”, they tend to re-combine at thesame rate as being fractured, or do not fracture effectively andtherefore no further reduction in the particle size is achieved.Critical sizes are specific to particular mills and sets of millingconditions.

Thus, manufacture of fine particles by milling can require much effortand there are factors which consequently place limits on the minimumsize of particles of active material which can be achieved, in practice,by such milling processes.

The present invention consequently relates to the provision of ahigh-energy impact process that is effective in producing improvementsin the resultant drug powders.

Furthermore, contrary to conventional thinking, the processes of thepresent invention do not need to be carried out in a closed system. Evenwhere the additive material being co-jet milled is leucine, there is noobserved loss of additive material or reduction in coating where the jetmilling is not carried out in a closed system. Rather, in one embodimentof the invention, the method of the present invention is carried out ina flow-through system, without any loss in performance of the resultantcomposite particles. This is an economically important feature, as itcan significantly increase the rate of production of the powders of theinvention.

In one embodiment of the present invention, 90% by mass of the activeparticles jet-milled are initially less than 20 μm in diameter. Morepreferably, 90% by mass of the active particles jet-milled are initiallyless than 10 μm in diameter, and most preferably less than 5 μm indiameter.

In another embodiment, 90% by mass of the additive particles jet-milledare initially less than 20 μm in diameter. More preferably, 90% by massof the additive particles jet-milled are initially less than 10 μm indiameter, and most preferably less than 5 μm in diameter or less than 3μm in diameter.

The terms “active particles” and “particles of active material” and thelike are used interchangeably herein. The active particles comprise oneor more pharmaceutically active agents. The preferred active agentsinclude:

1) steroid drugs such as alcometasone, beclomethasone, beclomethasonedipropionate, betamethasone, budesonide, clobetasol, deflazacort,diflucortolone, desoxymethasone, dexamethasone, fludrocortisone,flunisolide, fluocinolone, fluometholone, fluticasone, fluticasoneproprionate, hydrocortisone, triamcinolone, nandrolone decanoate,neomycin sulphate, rimexolone, methylprednisolone and prednisolone;

2) antibiotic and antibacterial agents such as metronidazole,sulphadiazine, triclosan, neomycin, amoxicillin, amphotericin,clindamycin, aclarubicin, dactinomycin, nystatin, mupirocin andchlorhexidine;

3) systemically active drugs such as isosorbide dinitrate, isosorbidemononitrate, apomorphine and nicotine;

4) antihistamines such as azelastine, chlorpheniramine, astemizole,cetirizine, cinnarizine, desloratadine, loratadine, hydroxyzine,diphenhydramine, fexofenadine, ketotifen, promethazine, trimeprazine andterfenadine;

5) anti-inflammatory agents such as piroxicam, nedocromil, benzydamine,diclofenac sodium, ketoprofen, ibuprofen, heparinoid, nedocromil,cromoglycate, fasafungine and iodoxamide;

6) anticholinergic agents such as atropine, benzatropine, biperiden,cyclopentolate, oxybutinin, orphenadine hydrochloride, glycopyrronium,glycopyrrolate, procyclidine, propantheline, propiverine, tiotropium,tropicamide, trospium, ipratropium bromide and oxitroprium bromide;

7) anti-emetics such as bestahistine, dolasetron, nabilone,prochlorperazine, ondansetron, trifluoperazine, tropisetron,domperidone, hyoscine, cinnarizine, metoclopramide, cyclizine,dimenhydrinate and promethazine;

8) hormonal drugs such as protirelin, thyroxine, salcotonin, somatropin,tetracosactide, vasopressin or desmopressin;

9) bronchodilators such as salbutamol, fenoterol and salmeterol;

10) sympathomimetic drugs such as adrenaline, noradrenaline,dexamfetamine, dipirefin, dobutamine, dopexamine, phenylephrine,isoprenaline, dopamine, pseudoephedrine, tramazoline and xylometazoline;

11) anti-fungal drugs such as amphotericin, caspofungin, clotrimazole,econazole nitrate, fluconazole, ketoconazole, nystatin, itraconazole,terbinafine, voriconazole and miconazole;

12) local anaesthetics such as amethocaine, bupivacaine, hydrocortisone,methylprednisolone, prilocaine, proxymetacaine, ropivacaine,tyrothricin, benzocaine and lignocaine;

13) opiates, preferably for pain management, such as buprenorphine,dextromoramide, diamorphine, codeine phosphate, dextropropoxyphene,dihydrocodeine, papaveretum, pholcodeine, loperamide, fentanyl,methadone, morphine, oxycodone, phenazocine, pethidine and combinationsthereof with an anti-emetic;

14) analgesics and drugs for treating migraine such as clonidine,codine, coproxamol, dextropropoxypene, ergotamine, sumatriptan, tramadoland non-steroidal anti-inflammatory drugs;

15) narcotic agonists and opiate antidotes such as naloxone, andpentazocine;

16) phosphodiesterase type 5 inhibitors, such as sildenafil (Viagra(trade mark));

17) antidepressants such as amesergide, amineptine, amitriptyline,amoxapine, benactyzine, brofaromine, bupropion, butriptyline,cianopramine, citalopram, clorgyline, clovoxamine, demexiptiline,desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, etoperidone,femoxetine, fezolamine, fluoxetine, fluvoxamine, ifoxetine, imipramine,iprindole, isocarboxazid, levoprotiline, lofepramine, maprotiline,medifoxamine, melitracen, metapramine, methylphenidate, mianserin,milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nialamide,nomifensine, nortriptyline, opipramol, oxaflozane, oxaprotiline,oxitriptan, paroxetine, phenelzine, pirlindole, propizepine,protriptyline, quinupramine, rolipram, selegiline, sertraline,setiptiline, sibutramine, teniloxazine, tianeptine, tofenacin,toloxatone, tranylcypromine, trazodone, trimipramine, tryptophan,venlafaxine, viloxazine, viqualine and zimeldine;

18) serotonin agonists such as 2-methyl serotonin, buspirone,ipsaperone, tiaspirone, gepirone, lysergic acid diethylamide, ergotalkaloids, 8-hydroxy-(2-N,N-dipropylamino)-tetraline,1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan,m-chlorophenylpiperazine, trazodone, zacopride and mezacopride;

19) serotonin antagonists including ondansetron, granisetron,metoclopramide, tropisetron, dolasetron, trimethobenzamide,methysergide, risperidone, ketanserin, ritanserin, clozapine,amitryptiline,R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol,azatadine, cyproheptadine, fenclonine, dexfenfluramine, fenfluramine,chlorpromazine and mianserin;

20) adrenergic agonists including methoxamine, methpentermine,metaraminol, mitodrine, clonidine, apraclonidine, guanfacine, guanabenz,methyldopa, amphetamine, methamphetamine, epinephrine, norepinephrine,ethylnorepinephrine, phenylephrine, ephedrine, pseudo-ephedrine,methylphenidate, pemoline, naphazoline, tetrahydrozoline, oxymetazoline,xylometazoline, phenylpropanolamine, phenylethylamine, dopamine,dobutamine, colterol, isoproterenol, isotharine, metaproterenol,terbutaline, metaraminol, tyramine, hydroxyamphetamine, ritodrine,prenalterol, albuterol, isoetharine, pirbuterol, bitolterol, fenoterol,formoterol, procaterol, salmeterol, mephenterine and propylhexedrine;

21) adrenergic antagonists such as phenoxybenzamine, phentolamine,tolazoline, prazosin, terazosin, doxazosin, trimazosin, yohimbine, ergotalkaloids, labetalol, ketanserin, urapidil, alfuzosin, bunazosin,tamsulosin, chlorpromazine, haloperidol, phenothiazines, butyrophenones,propranolol, nadolol, timolol, pindolol, metoprolol, atenolol, esmolol,acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, carvedilol,medroxalol, naftopidil, bucindolol, levobunolol, metipranolol,bisoprolol, nebivolol, betaxolol, carteolol, celiprolol, sotalol,propafenone and indoramin;

22) adrenergic neurone blockers including bethanidine, debrisoquine,guabenxan, guanadrel, guanazodine, guanethidine, guanoclor and guanoxan;

23) benzodiazepines including alprazolam, brotizolam, chlordiazepoxide,clobazepam, clonazepam, clorazepate, demoxepam, diazepam, estazolam,flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazapam,oxazepam, prazepam, quazepam, temazepam and triazolam;

24) mucolytics agents such as N-acetylcysteine, recombinant human DNase,amiloride, dextrans, heparin and low molecular weight heparin; and

25) pharmaceutically acceptable salts of any of the foregoing.

Preferably, the active agent is a small molecule, as opposed to amacromolecule. Preferably, the active agent is not a protein, and morepreferably, the active agent is not insulin. In the case of proteins andin particular insulin, there is little or no benefit to be derived fromthe use of a force control agent in a dry powder formulation foradministration by inhalation. The reason for this is that in the case ofthese active agents, the active agent itself acts as a force controlagent and the cohesive forces of particles of these active agents arealready only weak.

In preferred embodiments of the present invention, the active agent isheparin (fractionated and unfractionated), apomorphine, clobozam,clomipramine or glycopyrrolate.

The terms “additive particles” and “particles of additive material” areused interchangeably herein. The additive particles comprise one or moreadditive materials (or FCAs). Preferably, the additive particles consistessentially of the additive material.

Known additive materials usually consist of physiologically acceptablematerial, although the additive material may not always reach the lung.For example, where the additive particles are attached to the surface ofcarrier particles, they will generally be deposited, along with thosecarrier particles, at the back of the throat of the user.

Advantageously, the additive material includes one or more compoundsselected from amino acids and derivatives thereof, and peptides andderivatives thereof. Amino acids, peptides and derivatives of peptidesare physiologically acceptable and give acceptable release of the activeparticles on inhalation.

It is particularly advantageous for the additive material to comprise anamino acid. The additive material may comprise one or more of any of thefollowing amino acids: leucine, isoleucine, lysine, valine, methionine,and phenylalanine. The additive may be a salt or a derivative of anamino acid, for example aspartame or acesulfame K. Preferably, theadditive particles consist substantially of an amino acid, morepreferably of leucine, advantageously L-leucine. The D-and DL-forms mayalso be used. As indicated above, leucine has been found to giveparticularly efficient dispersal of the active particles on inhalation.

The additive material may include one or more water soluble substances.This helps absorption of the additive material by the body if it reachesthe lower lung. The additive material may include dipolar ions, whichmay be zwitterions. It is also advantageous to include a spreading agentas an additive material, to assist with the dispersal of the compositionin the lungs. Suitable spreading agents include surfactants such asknown lung surfactants (e.g. ALEC, Registered Trade Mark), whichcomprise phospholipids, for example, mixtures of DPPC (dipalmitoylphosphatidylcholine) and PG (phosphatidylglycerol).

The phospholipids used in accordance with the invention may have acylsubstituents on the phosphatidyl groups. As in their naturalcounterparts, the acyl groups may comprise identical or different,saturated or unsaturated acyl radicals, generally C14-22, especiallyC16-20, acyl radicals. Thus, the phospholipids may comprise, by way ofacyl radicals, the saturated radicals palmitoyl C16:0 and stearoyl C18:0and/or the unsaturated radicals oleoyls C18:1 and C18:2. Diacylsubstitution is preferred and the phospholipids used in the compositionsin accordance with the invention more particularly comprise twoidentical saturated acyl radicals, especially dipalmitoyl and distearoylor a mixture of phospholipids in which such radicals predominate, inparticular mixtures in which dipalmitoyl is the major diacy component.Thus, phosphatidyl choline (PC) and PG may be used may be used with thesame diacylphosphatidyl profile as in PC and PG extracted from human oranimal or vegetable sources, but if synthetic sources are used thedipalmitoyl component may predominate, as in the DPPC mentioned above.

Suitable surfactants include, for example, dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylinositol(DPPI). Further exemplary phospholipids include1-palmitoyl-2-oleoyl-SN-glycero-3-phosphoglycerol (POPG),phosphoglycerides such as disteroylphosphatidylcholine,diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine,diphosphatidylglycerol, short-chain phosphatidylcholines, long-chainsaturated phosphatidylethanolamines, long-chain saturatedphosphatidylserines, long-chain saturated phosphatidylglycerols,long-chain saturated phosphatidylinositols.

The additive material may comprise a phospholipid or a derivativethereof. Lecithin has been found to be a good material for the additivematerial.

The additive material may comprise a metal stearate, or a derivativethereof, for example, sodium stearyl fumarate or sodium stearyllactylate. Advantageously, the additive material comprises a metalstearate. For example, zinc stearate, magnesium stearate, calciumstearate, sodium stearate or lithium stearate. Preferably, the additivematerial comprises magnesium stearate.

The additive material may include or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble or water dispersible, forexample lecithin, in particular soya lecithin, or substantially waterinsoluble, for example solid state fatty acids such as oleic acid,lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, orderivatives (such as esters and salts) thereof such as glycerylbehenate. Specific examples of such materials are: phosphatidylcholines,phosphatidylethanolamines, phosphatidylglycerols and other examples ofnatural and synthetic lung surfactants; lauric acid and its salts, forexample, sodium lauryl sulphate, magnesium lauryl sulphate;triglycerides such as Dynsan 118 and Cutina HR; and sugar esters ingeneral. Alternatively, the additive may be cholesterol.

Other possible additive materials include sodium benzoate, hydrogenatedoils which are solid at room temperature, talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch.

In one embodiment of the invention, the additive material comprises anamino acid, a metal stearate or a phospholipid. Preferably, the additivematerial comprises one or more of L-, D- or DL-forms of leucine,isoleucine, lysine, valine, methionine, phenylalanine, or Aerocine,lecithin or magnesium stearate. In another embodiment, the additivematerial comprises leucine and preferably l-leucine.

In general, the optimum amount of additive material to be included in adry powder formulation will depend on the chemical composition and otherproperties of the additive material and of the active material, as wellas upon the nature of other particles, such as carrier particles, ifpresent. In general, the efficacy of the additive material is measuredin terms of the FPF of the composition.

In one embodiment of the present invention, composite active particlesproduced by co-jet milling according to the present invention are mixedwith carrier particles made of an inert excipient material.

Where the powder composition comprises an active material, additivematerial and excipient material, this is referred to as a 3-componentsystem. In contrast, a 2-component system comprises just active andadditive materials.

Excipient materials may be included in powders for administration bypulmonary inhalation for a number of reasons. On the one hand, theinclusion of particles of excipient material of an appropriate size canenhance the flow properties of the powder and can enhance the powder'shandleability. Excipient material is also added to powder formulationsas a diluent. It can be very difficult to accurately and reproduciblyadminister a very small amount of powder. Where low doses of drug arerequired, this can pose a problem and so it can be desirable to add adiluent to the powder, to increase the amount of powder to be dispensed.

In one embodiment of the present invention, the excipient material is inthe form of relatively large or coarse carrier particles.Advantageously, substantially all (by weight) of the carrier particleshave a diameter which lies between about 20 μm and about 1000 μm, morepreferably about 50 μm and about 1000 μm. Preferably, the diameter ofsubstantially all (by weight) of the carrier particles is less thanabout 355 μm and lies between about 20 μm and about 250 μm.

Preferably at least about 90% by weight of the carrier particles have adiameter between from about 40 μm to about 180 μm. The relatively largediameter of the carrier particles improves the opportunity for other,smaller particles to become attached to the surfaces of the carrierparticles and provides good flow and entrainment characteristics andimproved release of the active particles in the airways to increasedeposition of the active particles in the lung.

Conventional thinking regarding carrier particles is that they improvethe poor flowability of formulations comprising fine particles of lessthan 10 μm. The poor flowability is due to the agglomeration of the fineparticles which occurs due to the strong attractive forces between thesmall particles. In the presence of large carrier particles, theseattractive forces cause the fine particles to become attached to thesurface of the large carrier particles, forming (usually discontinuous)coatings. This arrangement of the large and fine particles leads tobetter flow characteristics than is observed with a formulation made upsolely of fine active particles.

The carrier particles to be added to the composite active particles ofthe present invention are relatively large particles of an excipientmaterial, such as lactose.

The ratios in which the carrier particles and composite active particlesare mixed will, of course, depend on the type of inhaler device used,the type of active particles used and the required dose. The carrierparticles may be present in an amount of at least about 50%, morepreferably at least about 70%, more preferably at least about 80%,advantageously at least about 90% and most preferably at least about95%, based on the combined weight of the composite active particles andthe carrier particles.

A 3-component system including carrier particles, such as the onedescribed above, would be expected to work well in a passive device. Thepresence of the carrier particles makes the powder easier to extractfrom the blister, capsule or other storage means. The powder extractiontends to pose more of a problem in passive devices, as they do notcreate as turbulent an air flow through the blister upon actuation asactive devices. This means that it can be difficult to entrain all ofthe powder in the air flow. The powder entrainment in a passive deviceis made easier where the powder includes carrier particles as this willmean that the powder is less cohesive and exhibits better flowability,compared with a powder consisting entirely of smaller particles, forexample all having a diameter of less than 10 μm.

Where carrier particles and the composite active particles madeaccording to the present invention are mixed, the active particlesshould readily release from the surface of the carrier particles uponactuation of the dispensing device by virtue of the additive material onthe surface of the active particles. This release may be furtherimproved where the carrier particles also have additive material appliedto their surfaces. This application can be achieved by simple gentleblending or co-milling, for example as described in WO 97/03649.

However, the combination of large carrier particles and fine activeparticles has its disadvantages. It can only be effectively used with arelatively low (usually only up to 5%) drug content. As greaterproportions of fine particles are used, more and more of the fineparticles fail to become attached to the large carrier particles andsegregation of the powder formulation becomes a problem. This, in turn,can lead to unpredictable and inconsistent dosing. The powder alsobecomes more cohesive and difficult to handle.

Furthermore, the size of the carrier particles used in a dry powderformulation can be influential on segregation.

Segregation can be a catastrophic problem in powder handling duringmanufacture and the filling of devices or device components (such ascapsules or blisters) from which the powder is to be dispensed.Segregation tends to occur where ordered mixes cannot be madesufficiently stable. Ordered mixes occur where there is a significantdisparity in powder particle size. Ordered mixes become unstable andprone to segregation when the relative level of the fine componentincreases beyond the quantity which can adhere to the larger componentsurface, and so becomes loose and tends to separate from the main blend.When this happens, the instability is actually exacerbated by theaddition of anti-adherents/glidants such as FCAs.

In the case of dry powder formulations of micron-sized drug, and typical60 to 150 μm sized carrier, this instability tends to occur once drugcontent exceeds a few percent, the exact amount is dependant on thedrug. However, it has been found that a carrier with a particle size of<30 μm tends not to exhibit this instability. This is thought to be dueto the fine carrier particles having relatively higher surface areacompared to the coarse carrier particles, and the similarity between thesize of the active particles and the carrier particles. Such finecarrier particles are not often used, mainly because of their poor flowcharacteristics, as discussed above.

According to another embodiment of the present invention, the3-component system comprises the composite active particles madeaccording to the present invention, together with fine excipientparticles. Such excipient particles have a particle size of 30 μm orless, preferably 20 μm or less and more preferably 10 i.im or less. Theexcipient particles advantageously have a particle size of 30 to 5 μm.

One would expect such a powder formulation, made up of only fineparticles with a particle size of less than 10 μm, to suffer from thecohesion and flowability problems observed with formulations comprisingjust fine active particles. The active particles do not coat the fineexcipient particles, as they do the large carrier particles, because ofthe different forces existing between fine particles and fine and largeparticles.

However, where the powder formulation comprises composite activeparticles according to the present invention and fine excipientparticles, it has been surprisingly found that such formulations areefficiently dispensed by an active device. It has been found that thepotentially poor flow characteristics or • handleability of powderscomprising only particles with a size of less than 10 μm are notsignificant when the powder is dispensed using an active inhaler device.

As mentioned above, the active device causes turbulence within theblister, capsule or other powder storage means. This means that evenpowders with fine excipient particles can be extracted. Furthermore, thepresence of the composite active particles means that the agglomeratesformed from the fine particles are not so stable that they are notbroken up upon actuation of the inhaler device. Thus, it has beensurprisingly found that compositions comprising the composite activeparticles of the present invention and fine particles of an inertexcipient material, such as lactose, can be efficiently dispensed usingan active inhaler device.

In another embodiment of the present invention, the fine excipientparticles added to the composite active particles are themselves co-jetmilled with additive material. The co-jet milling of the activeparticles with additive material and of the excipient particles withadditive material can occur separately or together, and by similar ordifferent forms of co-milling. For example, the active particles may beco-jet milled, the excipient particles may be co-processed by acompressive form of milling such as mechanofusion or similar processes,or visa versa. The quantities and nature of additives may be differentfor active and excipient. This may be the case where the two groups ofparticles have different sizes and hence relative surface areas.

Co-jet milling the fine excipient particles with the additive materialresults in coating of the additive material on the surfaces of theexcipient particles. This coating can further reduce the cohesiveness ofthe 3-component system and can further enhance deagglomeration uponactuation of the inhaler device.

Generally, flow of compositions comprising fine carrier particles ispoor unless they are pelletised (e.g. as is done in the AstraZenecaproduct OXIS (registered trade mark). However, using the processes ofthe present invention, fine lactoses (e.g. Sorbolac 400 with a particlesize of 1 to 15 μm) have been produced which flow sufficiently well foruse in DPIs with >5% drug, and up to approximately 30% and possibly 50%cohesive micronised drug. It should be noted that these beneficialproperties are achieved without the need to resort to pelletisation,which has its own disadvantages of being difficult to do and generallydecreasing FPFs.

Thus, the co-milling of the fine excipient particles and additivematerial in accordance with the present invention allows one to produceblends of active and excipient materials with a much greater range ofactive agent content than is possible using conventional carrierparticles (i.e. >5%). The resultant dry powder formulations also benefitfrom improved aerosolisation.

In the present invention, different grinding and injection pressures maybe used in order to produce particles with different coatingcharacteristics. The invention also includes embodiments where differentgrinding and injection pressures are combined, to produce compositeparticles with desired properties, that is, to engineer the particles.

Co-jet milling may be carried out at grinding pressures between 0.1 and12 bar. Varying the pressure allows one to control the degree ofparticle size reduction. At pressures in the region of 0.1-3 bar, morepreferably 0.5-2 bar and most preferably 1-2 bar, the co-jet millingwill primarily result in blending of the active and additive particles,so that the additive material coats the active particles. On the otherhand, at 3-12 bar, and preferably 5-12 bar, the co-jet milling willadditionally lead to particle size reduction.

In one embodiment, the jet milling is carried out at a grinding pressureof between 0.1 and 3 bar, to achieve blending of the active and additiveparticles. As discussed below in greater detail, when the co-jet millingof the present invention is carried out at such relatively lowpressures, the resultant particles have been shown to perform well whendispensed using passive devices. It is speculated that this is becausethe particles are larger than those produced by co-jet milling at higherpressures and these relatively larger particles are more easilyextracted from the blister, capsule or other storage means in thepassive device, due to less cohesion and better flowability. Whilst suchrelatively large particles are easily extracted from the blister orcapsule in an active device, they may result in throat deposition.

In another embodiment, the jet milling is carried out at a grindingpressure of between 3 and 12 bar, to achieve a reduction of the sizes ofthe active and additive particles. The co-jet milling at theserelatively high pressures can produce extremely small composite activeparticles having an MMAD of between 3 and 0.5 μm. These fine particlesizes are excellent for deep lung deposition, but they really need to bedispensed using an active inhaler device, as the powder formulationscomprising such fine particles are actually rather “sticky”. Asdiscussed below, this stickiness may not pose a problem for activedevices and is actually thought to be advantageous as it can slow theextraction of the powder so that the composite active particles travelmore slowly in the powder plume generated by the device, therebyreducing throat deposition.

Tests were carried out whereby pre-micronised lactose (as a drug model)was co-jet milled in an MC50 Hosakawa Micron with 5% magnesium stearate.At 2 bar milling pressure, the resultant material had a d(50) ofapproximately 3 μm, whilst milling the same mixture at around 7 barresulted in material with a d(50) of about 1 μm. Thus, when operatingwith a jet milling pressure of 0.1-3 bar little milling, that it isparticle size reduction, is seen. From 3-12 bar milling pressure,increasing milling is seen, with the particle size reduction increasingwith the increasing pressure. This means that the milling pressure maybe selected according to the desired particle size in the resultantmixture. In one embodiment, the step of jet milling is carried out at aninlet pressure between 0.1 and 3 bar. Alternatively, the step of jetmilling is carried out at an inlet pressure of between 3 and 12 bar.

As indicated above, co-jet milling at lower pressures produces powderswhich perform well in passive devices whilst powders milled at higherpressures perform better in active devices, such as Aspirair (trademark).

The co-jet milling processes according to the present invention can alsobe carried out in two or more stages, to combine the beneficial effectsof the milling at different pressures and/or different types of millingor blending processes. The use of multiple steps allows one to tailorthe properties of the co-jet milled particles to suit a particularinhaler device, a particular drug and/or to target particular parts ofthe lung.

In one embodiment, the milling process is a two-step process comprisingfirst jet-milling the drug on its own at high grinding pressure toobtain the very small particle sizes possible using this type ofmilling. Next, the milled drug is co-jet milled with an additivematerial. Preferably, this second step is carried out at a lowergrinding pressure, so that the effect is the coating of the small activeparticles with the additive material.

The additive material may also be milled on its own prior to theco-milling step. This milling may be conducted in a jet mill, a ballmill, a high pressure homogeniser or alternative known ultrafine millingmethods. The particles of additive material are preferably in a formwith 90% of the particles by mass of diameter<10 μm, more preferably <5μm, more preferably <2 μm, more preferably <1 μm and most preferably<0.5 μm.

This two-step process produces better results than simply co-jet millingthe active material and additive material at a high grinding pressure.Experimental results discussed below show that the two-step processresults in smaller particles and less throat deposition than simpleco-jet milling of the materials at a high grinding pressure.

In another embodiment of the present invention, the particles producedusing the two-step process discussed above subsequently undergomechanofusion or an equivalent compressive process. This finalmechanofusion step is thought to “polish” the composite activeparticles, further rubbing the additive material into the particles.This allows one to enjoy the beneficial properties afforded to particlesby mechanofusion, in combination with the very small particles sizesmade possible by the co-jet milling.

The reduction in particle size may be increased by carrying out theco-jet milling at lower temperatures. Whilst the co-jet milling processmay be carried out at temperatures between −20° C. and 40° C., theparticles will tend to be more brittle at lower temperatures, and theytherefore fracture more readily so that the milled particles tend to beeven smaller. Therefore, in another embodiment, the jet milling iscarried out at temperatures below room temperature, preferably at atemperature below 10° C., more preferably at a temperature below 0° C.

Preferably, all of the particles are of a similar size distribution.That is, substantially all of the particles are within the size range ofabout 0 to about 5 μm, of about 0 to about 20 μm, of about 0 to 10 μm,of about 0 to 5 μm or of about 0 to 2 μm.

In accordance with a second aspect of the present invention, apharmaceutical dry powder composition for pulmonary inhalation isprovided, comprising composite active particles made by a methodaccording to the first aspect of the invention.

The MMAD of the composite active particles is preferably not more than10 μm, and advantageously it is not more than 5 μm, more preferably notmore than 3 μm, even more preferably not more than 2 μm, more preferablynot more than 1.8 μm more preferably not more than 1.5 μm, even morepreferably not more than 1.2 μm and most preferably not more than 1 μm.

Accordingly, advantageously at least 90% by weight of the compositeactive particles have a diameter of not more than 10 μm, advantageouslynot more than 5 μm, preferably not more than 3 μm, even more preferablynot more than 2.5 μm, even more preferably not more than 2 μm and morepreferably not more than 1.5 μm, or even not more than 1.0 μm.

It is an aim of the present invention to optimise the powder properties,so that the FPF and FPD are improved compared to those obtained usingknown powder formulations, regardless of the type of device used todispense the composition of the invention.

It is a particular aim of the present invention to provide a dry powderformulation which has an FPF of at least 40%. Preferably, the FPF(ED)will be between 60 and 99%, more preferably between 70 and 99%, morepreferably between 80 and 99% and even more preferably between 90 and99%. Furthermore, it is desirable for the FPF(MD) to be at least 40%.Preferably, the FPF(MD) will be between 40 and 99%, more preferablybetween 50 and 99%, more preferably between 60 and 99%, and morepreferably between 70 and 99% and even more preferably between 80 and99%.

In a preferred embodiment of the present invention the resultant drypowder formulation has a reproducible FPF(ED) of at least 70%.Preferably, the FPF(ED) will be at least 80%, more preferably theFPF(ED) will be at least 85%, and most preferably the FPF(ED) will be atleast 90%.

In a further preferred embodiment, the dry powder formulation has areproducible FPF(MD) of at least 60%. Preferably, the FPF(MD) will be atleast 70%, more preferably the FPF(MD) will be at least 80%, and mostpreferably the FPF(MD) will be at least 85%.

As illustrated by the experimental results set out below, it has beensurprisingly found that co-milling active particles with additiveparticles using jet milling results in composite active particles havingsignificantly better FPF and FPD than those produced by co-milling usingmechanofusion, when the powders are dispensed using the active inhalerdevice Aspirair (trade mark).

This unexpected improvement in the FPF and FPD of the powderformulations prepared is thought to be due to the following factors.Firstly, the milling process results in very small particles. Secondly,there appears to be only partial coverage of the particles with theforce control agent and this means that some of the particle cohesion isretained, affording better powder handleability despite the very smallparticle sizes.

Co-jet milling has surprisingly been found to be capable ofsignificantly reducing the median primary particle size of activeparticles (for example, from 3 or 2 μm to 1 μm), while also allowinggood aerosolisation from a delivery device. This further reduction inprimary particle size is considered to be advantageous for delivery ofsystemically targeted molecules to the deep lung. The benefit here is toco-jet mill active particles with additive particles in order to reduceprimary particle size while still achieving a reduction in the level ofpowder cohesion and adhesion by coating the particles for additivematerial.

Test Methods

All materials were evaluated in the Next Generation Impactor (NGI).Details of the test are provided in each case.

Formulations were processed using:

1) The Hosokawa Micron MechanoFusion AMS Mini system. This system wasoperated with a novel rotor, providing a 1mm compression gap; and

2) The Hosokawa Micron AS50 spiral jet mill.

The in-vitro testing was performed using an Aspirair (trade mark)device, which is an active inhaler device.

The formulations were composed of one or more of the followingconstituents:

Magnesium stearate (standard grade)

L-Leucine (Ajinomoto) and jet milled by Micron Technologies

Sorbolac 400 lactose

Micronised clobozam

Micronised apomorphine hydrochloride

Micronised lactose

Re-condensed Leucine (Aerocine)

Comparison of Co-Jet Milled and Mechanofused Formulations (Clobozam)

The following is a comparison of 2-component systems comprising co-jetmilled or mechanofused active particles and additive material.

1.01 g of micronised clobozam was weighed out, and then gently pressedthrough a 300 μm metal sieve, using the rounded face of a metal spatula.This formulation was recorded as “3A”.

9.37 g of micronised clobozam was then combined with 0.50 g ofmicronised L-leucine in the MechanoFusion system. The material wasprocessed at a setting of 20% power for 5 minutes, followed by a settingof 80% power for 10 minutes. This material was recorded as “4A”. Afterblending, this powder was then gently pushed through a 300 μm metalsieve with a spatula. This material was recorded as “4B”.

9.57 g of micronised clobozam was then combined with 0.50 g of magnesiumstearate in the MechanoFusion system. The material was processed at asetting of 20% power for 5 minutes, followed by a setting of 80% powerfor 10 minutes. This material was recorded as “5A”. After blending, thispowder was rested overnight, and then was gently pushed through a 300 μmmetal sieve with a spatula. This material was recorded as “5B”.

9.5 g of micronised clobozam was then combined with 0.50 g of micronisedL-leucine in the MechanoFusion system. The material was processed at arelatively low speed setting of 20% power for 5 minutes. This processwas intended only to produce a good mix of the components. This materialwas recorded as “6A”.

6.09 g of “6A” fed at approximately 1 g per minute into an AS50 spiraljet mill, set with an injector pressure of about 7 bar and a grindingpressure of about 5 bar. The resulting material was recovered andrecorded as “6B”.

After milling, this powder was rested overnight, and then was gentlypushed through a 300 μm metal sieve with a spatula. This material wasrecorded as “6C”.

9.5 g of micronised clobozam was then combined with 0.50 g of magnesiumstearate in the MechanoFusion system. The material was processed at asetting of 20% power for 5 minutes. This material was recorded as “7A”.

6.00 g of “7A” was fed at approximately 1 g per minute into the AS50spiral jet mill, set with an injector pressure of about 7 bar and agrinding pressure of about 5 bar. The resulting material was recoveredand recorded as “7B”.

After milling, this powder was gently pushed through a 300 μm metalsieve with a spatula. This material was recorded as “7C”.

A batch of re-condensed leucine (also referred to as “Aerocine”) wasproduced by subliming to vapour a sample of leucine in a tube furnace,and re-condensing as a very finely dispersed powder as the vapourcooled. This batch was identified as “8A”.

9.5 g of micronised clobozam was then combined with 0.50 g of Aerocine,in the MechanoFusion system. The material was processed at a setting of20% power for 5 minutes, followed by a setting of 80% power for 10minutes. This material was recorded as “8B”. After blending, this powderwas rested overnight, and then was gently pushed through a 300 μm metalsieve with a spatula. This material was recorded as “8C”.

9.5 g of micronised clobozam was combined with 0.50 g of Aerocine in theMechanoFusion system. The material was processed at a setting of 20%power for 5 minutes. 7.00 g of this powder was then fed into the AS50spiral jet mill, set with an injector pressure of about 7 bar and agrinding pressure of about 5 bar. The resulting material was recoveredand recorded as “9A”.

After milling, this powder was gently pushed through a 300 μm metalsieve with a spatula. This material was recorded as “9B”.

A number of foil blisters were filled with approximately 2 mg of thefollowing clobozam formulations:

3A—no milling & no additive material

4B—leucine & mechanofused

5B—magnesium stearate & mechanofused

6C—leucine & co-jet milled

7C—magnesium stearate & co-jet milled

8C—Aerocine & co-jet milled

9B—Aerocine & mechanofused.

These formulations were then fired from an Aspirair device into an NGIat a flow rate of 60 l/m. The Aspirair was operated under 2 conditionsfor each formulation: with a reservoir of 15 ml of air at 1.5 bar orwith a reservoir of 30 ml of air at 0.5 bar.

Full details of the results are attached. The impactor test results aresummarised in Tables 1, 2 and 3 below.

TABLE 1 FPD (mg) Formulation MD (mg) ED (mg) (<5 μm) MMAD 3A 2.04 1.120.88 2.91 0.5 bar 30 ml 3A 1.92 1.74 1.23 2.86 1.5 bar 15 ml 4B 1.841.48 0.82 3.84 0.5 bar 30 ml 4B 1.80 1.56 0.81 3.32 1.5 bar 15 ml 5B1.84 1.53 1.17 2.34 0.5 bar 30 ml 5B 1.85 1.55 1.12 2.22 1.5 bar 15 ml6C 1.93 1.80 1.67 2.11 0.5 bar 30 ml 1.86 1.73 1.62 2.11 6C 1.97 1.861.67 2.07 1.5 bar 15 ml 6C 1.74 1.65 1.46 2.03 1.5 bar 15 ml (siliconcoated plates) 7C 2.06 1.99 1.87 1.97 0.5 bar 30 ml 7C 1.89 1.78 1.631.79 1.5 bar 15 ml 8C 1.82 1.73 1.62 2.02 0.5 bar 30 ml 8C 1.81 1.741.57 2.01 1.5 bar 15 ml 9B 1.88 1.73 1.04 3.48 0.5 bar 30 ml 9B 1.801.64 0.94 3.12 1.5 bar 15 ml

TABLE 2 FPF FPF FPF FPF FPF (MD) (ED) (ED) (ED) (ED) % % % % %Formulation (<5 μm) (<5 μm) (<3 μm) (<2 μm) (<1 μm) 3A 43 78 49 32 170.5 bar 30 ml 3A 64 71 45 24 6 1.5 bar 15 ml 4B 45 55 28 15 7 0.5 bar 30ml 4B 45 52 30 18 9 1.5 bar 15 ml 5B 64 77 54 42 30 0.5 bar 30 ml 5B 6172 52 38 25 1.5 bar 15 ml 6C 87 93 77 44 8 0.5 bar 30 ml 87 94 76 44 96C 85 90 73 44 10 1.5 bar 15 ml 6C 84 89 74 45 8 1.5 bar 15 ml (siliconcoated plates) 7C 91 94 79 50 14 0.5 bar 30 ml 7C 86 92 82 56 16 1.5 bar15 ml 8C 89 93 79 48 12 0.5 bar 30 ml 8C 87 90 76 46 9 1.5 bar 15 ml 9B55 60 34 24 15 0.5 bar 30 ml 9B 52 57 34 24 15 1.5 bar 15 ml

TABLE 3 Formulation *recovery *throat *blister *device 3A 102% 3% 1% 43%0.5 bar 30 ml 3A 96% 15% 1% 8% 1.5 bar 15 ml 4B 97% 15% 7% 12% 0.5 bar30 ml 4B 95% 27% 6% 8% 1.5 bar 15 ml 5B 97% 7% 13% 4% 0.5 bar 30 ml 5B98% 14% 12% 4% 1.5 bar 15 ml 6C 97% 2% 1% 6% 0.5 bar 30 ml 101% 3% 1% 5%6C 104% 6% 3% 3% 1.5 bar 15 ml 6C 91% 8% 1% 4% 1.5 bar 15 ml (siliconcoated plates) 7C 110% 2% 1% 3% 0.5 bar 30 ml 7C 99% 6% 2% 3% 1.5 bar 15ml 8C 99% 3% 1% 4% 0.5 bar 30 ml 8C 95% 6% 1% 3% 1.5 bar 15 ml 9B 96%16% 2% 7% 0.5 bar 30 ml 9B 95% 26% 4% 5% 1.5 bar 15 ml

From these results it can be seen that the co-jet milled formulationsexhibited exceptional FPFs when dispensed from an active dry powderinhaler device. The FPFs observed were significantly better that thoseof the mechanofused formulations and those formulations which did notinclude an additive material. This improvement would appear to belargely due to reduced throat deposition, which was less than 8% for theco-jet milled formulations, compared to 15% for the pure drug and up to27% for the mechanofused formulations.

The reproducibility of the FPFs obtained was also tested. Through lifedose uniformity for the primary candidate, 6C, the preparation of whichis described above, was tested by firing 30 doses, with the emitteddoses collected by DUSA. Through life dose uniformity results arepresented in the graph of FIG. 8.

The mean ED was 1965 μg, with an RSD (relative standard deviation) of2.8%. This material consequently demonstrated excellent through lifedose reproducibility.

The particle size distributions of these powdered materials indicateboth the level of size reduction obtained by the co-milling, and thelevel of dispersion efficiency at varied pressures. The d(50) and d(97)plots provide a further indication of this dispersibility of the powdersas a function of pressure.

Formulation 5B exhibited much the best dispersion.

This set of dispersibility tests shows that the MechanoFused powdersdisperse more easily at lower pressures than the original drug, and thatmagnesium stearate gives the best dispersion within these, followed byAerocine and leucine. The co-jet milled powders do not appear todisperse any more easily in this test than the original drug, howeverthe primary particle sizes (d(50)) are reduced.

Comparison of Co-Jet Milled and Mechanofused Formulations (Apomorphine)

In order to establish the effect of co-jet milling on different activeagents, apomorphine hydrochloride formulations with fine carrierparticles (i.e. a 3-component system) were prepared and tested.

19.0 g of Sorbolac 400 lactose and 1.0 g of micronised L-leucine werecombined in the MechanoFusion system. The material was processed at asetting of 20% power for 5 minutes, followed by a setting of 80% powerfor 10 minutes. This material was recovered and recorded as “2A”.

15.0 g of apomorphine hydrochloride and 0.75 g of micronised L-leucinewere combined in the MechanoFusion system. The material was processed ata setting of 20% power for 5 minutes, followed by a setting of 80% powerfor 10 minutes. This material was recovered and recorded as “2B”.

2.1 g “2B’ plus 0.4 g micronised leucine were blended by hand in amortar and pestle for 2 minutes. 2.5 g micronised lactose was added andblended for a further 2 minutes. 5 g micronised lactose was added andblended for another 2 minutes. This mixture was then processed in theAS50 Spiral jet mill using an inlet pressure of 7 bar and a grindingpressure of 5 bar, feed rate 5 ml/min. This powder was gently pushedthrough a 3001.im metal sieve with a spatula. This material was recordedas “10A”.

1.5 g “10A” was combined with 0.20 g micronised L-leucine and 3.75 g ofSorbolac 400 lactose by hand in a mortar with a spatula for 10 minutes.This powder was gently pushed through a 300 μm metal sieve with aspatula. This material was recorded as “10B”.

9 g micronised apomorphine HCl plus 1 g micronised leucine were placedin the MechanoFusion system and processed at 20% (1000 rpm) for 5minutes. This initial blend was then processed in the AS50 Spiral jetmill using an inlet pressure of 7 bar and a grinding pressure of 5 bar,feed rate 5 ml/min This material was recorded as “11A”.

After blending, this powder was rested overnight, and then was gentlypassed through a 300 μm metal sieve by shaking. This material wasrecorded as “11B”.

2 g micronised apomorphine HCl plus 0.5 g micronised leucine wereblended by hand in mortar and pestle for 2 minutes. 2.5 g micronisedlactose was added and blended for a further 2 minutes. Then 5 gmicronised lactose was added and blended for another 2 minutes. Thismixture was then processed in the AS50 Spiral jet mill using an inletpressure of 7 bar and a grinding pressure of 5 bar, feed rate 5 ml/min.This powder was gently pushed through a 300 μm metal sieve with aspatula. This material was recorded as “12A”.

16.5 g of Sorbolac 400 and 0.85 g of micronised leucine were placed inthe MechanoFusion system and processed at 20% (1000 rpm) for 5 minutesthen at 80% (4000 rpm) for 10 minutes. This material was recorded as“13A”.

0.5 g micronised apomorphine HCl plus 2.0 g “13A” were blended by handin a mortar with a spatula for 10 minutes. This powder was gently pushedthrough a 300 μm metal sieve with a spatula. This material was recordedas “13B”.

A number of foil blisters were filled with approximately 2 mg of thefollowing formulations:

10A—20% apomorphine HCl, 5% l-leucine, 75% micronised lactose (co-jetmilled)

10C—26.2% apomorphine HCl, 5% l-leucine, 68.7% sorbolac (geometric)

11B—95% apomorphine HCl, 5% l-leucine (co-jet milled)

12A—20% apomorphine HCl, 5% leucine, 75% micronised lactose (all co-jetmilled)

13B—20% apomorphine HCl, 5% l-leucine, 75% Sorbolac 400 (leucine &Sorbolac mechanofused)

These were then fired from an Aspirair device into an NGI at a flow rateof 60 l/m. The Aspirair was operated with a reservoir of 15 ml at 1.5bar. Each in vitro test was conducted once to screen, and then theselected candidates were repeated. Further candidates were also repeatedin ACI at 60 l/m.

TABLE 4 FPD (μg) Formulation MD (μg) ED (μg) (<5 μm) MMAD 10A  384  356 329 1.78 13B  359  327  200 1.54 (1793) (1635) (1000) 10C  523  492 374 1.63 11B 1891 1680 1614 1.36 1882 1622 1551 1.44 1941 1669 16011.49 Ave. 1905 1657 1589 1.43 SD  32  31  33 0.07 RSD    1.7    1.9   2.1 4.6 11B 1895 1559 1514 1.58 1895 1549 1485 1.62 1923 1565 15041.62 ACI Ave. 1904 1558 1501 1.61 SD  16   8  15 0.02 RSD   1   1   1 112A  414  387  363 1.63  410  387  363 1.66  406  378  355 1.68 Ave. 410  384  360 1.66 SD   4   5   5 0.03 RSD   1   1   1 2 Total ave.2050 1920 1800 12A  395  365  341 1.80  411  385  360 1.85  400  370 349 1.84 ACI Ave.  402  373  350 1.83 SD   8  10  10 0.04 RSD   2   3  3 2 Total ave. 2011 1866 1750

TABLE 5 Formulation FPF FPF FPF FPF FPF 2 mg, 1.5 bar (MD) (ED) (ED)(ED) (ED) 15 ml reservoir % % % % % 60 l/min (<5 μm) (<5 μm) (<3 μm) (<2μm) (<1 μm) 10A 86 93 87 60 13 13B 56 61 52 42 19 10C 72 76 67 51 16 11B85 96 95 81 24 82 96 93 77 22 82 96 92 74 20 Ave. 83 96 93 77 22 SD 01.5 3.5 2 RSD 0 1.6 4.5 9.1 11B 80 97 94 74 14 78 96 93 70 14 78 96 9472 12 ACI Ave. 79 96 94 72 13 SD 1 1 2 1 RSD 1 1 3 9 12A 88 94 89 68 1389 94 89 66 12 87 94 88 64 12 Ave. 88 94 89 66 12 SD 0 1 2 1 RSD 0 1 3 512A 86 94 85 57 9 88 93 84 55 8 87 94 85 56 8 ACI Ave. 87 94 85 56 8 SD1 1 1 1 RSD 1 1 2 7

TABLE 6 Formulation 2 mg, 1.5 bar 15 ml reservoir 60 l/min RecoveryThroat Blister Device 10A 96% 5% 0.3% 7% 13B 94% 29%    3% 6% 10C 100%16%    2% 4% 11B 101% 2% 0.6% 10% 99% 2% 0.2% 14% 102% 2% 0.3% 14% Ave.101% 2% 0.4% 13% SD   1.5 0 0.2   2.3 RSD   1.5 0 57   18  11B 100% 1%0.5% 17% 100% 2% 0.1% 18% 101% 2% 0.4% 18% ACI Ave. 100% 2% 0.3% 18% SD1 1 0.2 1 RSD 1 35  62   3 12A 109% 4% 0.3% 6% 108% 4% 0.2% 6% 107% 4%0.02%  7% Ave. 108  4% 0.2 6% SD 1 0 0.1 1 RSD 1 0 82   9 12A 104% 3%0.4% 7% 108% 4% 0.2% 6% 105% 2% 0.4% 7% ACI Ave. 106% 3% 0.3 7% SD 2 10.1 1 RSD 2 33  35   9

The co-jet milled formulations once again exhibited exceptional FPFswhen it is dispensed using an active dry powder inhaler device. Theimprovement appears to be largely due to reduced throat deposition whichwas less than 5%, compared to between 16 and 29% for the mechanofusedformulations. “12A” was produced as a repeat of “10A”, but excluding themechanofused pre-blend (to show it was not required).

The reproducibility of the FPFs obtained with the formulation 12A, thepreparation of which is described above, was tested.

A number of foil blisters were filled with approximately 2 mg offormulation 12A. Through life dose uniformity was tested by firing 30doses, with the emitted doses collected by DUSA. Through life doseuniformity results are presented in the graph in FIG. 2.

The mean ED was 389 μg, with an RSD of 6.1% and the through lifedelivery of this drug-lactose formulation was very good.

In order to investigate the cause of the unexpected differences betweenthe co-jet milled formulations and those prepared by mechanofusion,formulations “11B”, “10A” and “2C” were fired from an Aspirair and plumeand vortex behaviour recorded on digital video. The images were studiedin light of the above differences in throat deposition.

Video of plume behaviour indicated a difference between the co-jetmilled formulations and mechanofused formulations. Mechanofusedformulations showed a highly concentrated fast moving bolus at the frontof the air jet. Most powder appeared to have been emitted afterapproximately 40 ms. Co-jet milled formulations showed a greater spreadof the plume. The plume front moves at a similar velocity, but the frontis less concentrated, appears to slow more quickly and powder is emittedfor considerably longer (i.e. >200 ms).

Video of the vortex showed that the mechanofused powders enter thevortex within 10 ms, whereas co-jet milled formulations take at least 30ms. Similarly the mechanofused powders appeared quicker to leave thevortex, with the co-jet milled materials forming a more prolongedfogging of the vortex. The behaviour observed for co-jet milledmaterials was described as an increased tendency to stick, but thenscour from the inside of the vortex.

Particle size distributions of the raw materials and selectedformulations were determined by Malvern particle sizer, via the Scirrocodry powder disperser. The data are summarised in the graphs shown inFIGS. 3 to 10.

FIG. 3 shows the particle size distribution of the raw materialmicronised lactose.

FIG. 4 shows the particle size distribution of the raw materialapomorphine.

FIG. 5 shows the particle size distribution of the raw materialclobozam.

FIG. 6 shows the particle size distribution of the clobozam formulationcomprising 95% clobozam and 5% mechanofused magnesium stearate.

FIG. 7 shows the particle size distribution of the clobozam formulationcomprising 95% clobozam and 5% co-jet milled Aerocine.

FIG. 8 shows the particle size distribution of the clobozam formulationcomprising 95% clobozam and 5% co-jet milled leucine.

FIG. 9 shows the particle size distribution of the apomorphineformulation comprising 75% lactose, 20% apomorphine and 5% co-jet milledleucine.

Finally, FIG. 10 also shows the particle size distribution of theapomorphine formulation comprising 75% lactose, 20% apomorphine and 5%co-jet milled leucine.

Where clobozam is co-jet milled with an additive material, a significantdrop in particle size is observed. This is not seen for the clobozammechanofused formulation here.

With the apomorphine-lactose co-milled materials, the size distributionis low (d(50) 1.8 to 1.6), when compared to the particle sizedistribution of the micronised lactose which comprises 75% of thecomposition. However, size reduction is not detectable with respect topure apomorphine, although it should be noted that this comprises only20% of the powder composition.

In vitro data confirm that, surprisingly, mechanofusion of activeparticles increased the throat deposition substantially. Mechanofusionhas previously been associated with improvement in dispersibility from apassive device, and reduced throat deposition. In this case,mechanofusion with magnesium stearate gives slightly lower throatdeposition than mechanofusion with leucine.

The throat deposition appears especially high for mechanofusedformulations containing leucine. It is speculated that this could be dueto an agglomerating affect during mechanofusion specific to leucine andnot magnesium stearate, or an electrostatic effect specific to leucine.

However, surprisingly co-jet milling produces materials which, incomparison, give very low throat deposition, low device deposition andexcellent dispersion from an active device. This co-jet milling alsoproduces a significant further size reduction, for example, d(50)changes from about 2.6 μm to about 1 μm for clobozam. When these factorsare combined, a remarkable aerosolisation performance is obtained fromthe in-vitro tests. FPF(ED) are 90 to 96%. This excellent performancewas obtained for leucine, Aerocine and magnesium stearate, and for 3different formulations, including 2 different active agents, with orwithout lactose diluent.

The consequence of this is the achievement of a very low oropharangealdeposition to the patient, typically of approximately 5%. Given thatboth throat and upper airway deposition (corresponding to impactorthroat and upper impactor stages) is reduced to a minimum, this willalso result in a minimised tasteable component, and minimised fractiondelivered to the GI tract. This corresponds to a 4-fold reduction incomparison to formulations without additive material.

It was noted that the co-jet milled materials were highly agglomeratedin appearance, in contrast to the mechanofused blends, which appeared asmore free flowing powders.

Studies suggest that the difference between the performance of theco-jet milled and mechanofused compositions is most apparent when theformulations are dispensed using an active device, such as Aspirair.Video of plume behaviour provided some indication of the reason fordifferences between the co-jet milled formulations and mechanofusedformulations. Mechanofused formulations showed a short fast bolus,whereas co-jet milled formulations showed a more drawn out plume. The“enhanced” flow properties of the mechanofused powders appear to explaintheir worse Aspirair performance. A degree of powder hold-up within thedevice appears to be beneficial, allowing a less dense and extendedplume to occur.

These video observations suggest the throat deposition difference isrelated to the powder lifetime within the vortex, with a longer lifetimegiving reduced throat deposition. Lower aerosol concentration at theplume front, lower momentum of aerosol plume (with lower cloud densityand smaller particle size) and greater opportunity to be de-agglomeratedare possible contributors to this improvement. Also, there is also morematerial in the later, slower part of the plume. Furthermore, lowerpowder density in the cyclone appears to lead to better dispersion.

It is speculated that the fact that the powder formulations aredifficult to extract from the blister actually enhances their deliverycharacteristics. It slows the extraction of the powder and so the activeparticles are travelling slower when they are expelled from thedispensing device. This means that the active particles do not travel atthe front of the plume of powder created when the device is actuated andthis means that the active particles are significantly less likely toimpact on the throat of the user. Rather, the active particles arethought to be further back in the plume, which allows them to be inhaledand administered to the lung. Naturally, too much blister retention willbe undesirable, as it will result in active agent remaining in thedevice after actuation.

In general, the co-milling of active particles with additive particleshas yielded reduced device/blister retention compared to formulationsprepared without additive particles. Mechanofusion was shown to givesignificantly greater blister retention than co-jet milling. The worstblister retention was seen for mechanofused clobozam with magnesiumstearate (13%). This appears related to the dusting nature of suchformulations. The mechanofused powders spread and flow more easily,which facilitates higher degrees of contact with the surfaces in bulkpowder contact. The co-milled powders however are heavily agglomerated,so contact with surfaces is much reduced, and dust residues are alsomuch less. The device retention also appears greater for mechanofusedthan co-jet milled powders for clobozam. However, the device retentionof apomorphine HCl co-jet milled with leucine appears notably high, at13%. Device and blister retention does not appear substantiallydifferent between the 0.5 and 1.5 bar tests, except for the case of theunaltered pure clobozam, where device retention approaches 50% for the0.5 bar test.

The tendency of a powder formulation to stick in the blister can beovercome in active devices, where a significant amount of turbulence iscreated within the blister when the device is actuated. However, this isnot the case in a passive device. Therefore, the tendency of aformulation to stick in the blister will have a detrimental effect onthe performance of a powder administered using a passive device. Thatsaid, as the active particles in the powder dispensed by a passivedevice are generally not moving as quickly as they would if dispensed byan active device, the problem of throat deposition (usually a result ofthe active particles travelling at the front of the powder plume) is notso great. Thus, it is clear that the properties of the active particlesneed to be tailored to the type of device used to dispense the powder.

Tests were carried out to compare the FPF achieved when the co-jetmilled compositions are dispensed using passive and active devices. Theexperiments used a lactose model fired into a TSI. The results were asfollows:

TABLE 7 FPF (MD) % FPF (MD) % Formulation FPF (ED) % (Cyclohaler)(Aspirair) Micronised lactose 32 18 — With 5% magnesium stearate 35 3227 (MgSt) in a conventional blender 5% MgSt jet-milled at 2 bar 68 53 625% MgSt jet-milled at 7 bar 52 39 72 5% MgSt mechanofused 69 57 49

This shows that jet milled material which has been co-jet milled at lowpressure is better in passive devices whilst high pressure jet milledmaterials perform better in active devices such as Aspirair.

Co-Jet Milled Clomipramine Hydrochloride Formulations in Aspirair

Clomipramine hydrochloride was obtained in powdered form. Force controlagents leucine and magnesium stearate were used.

Twelve formulations were produced from the original powder, using theHosokawa AS50 jet mill. Either the pure drug was passed through the millor a blend of drug with 5% w/w of a force control agent added. The millwas used with a range of parameters. Primarily, these were injector airpressure, grinding air pressure and powder feed rate.

Formulation 14: The pure clomipramine hydrochloride was passed throughthe microniser three times, each time with an injector air pressure of 8bar, grinding air pressure of 1.5 bar and powder feed rate of ˜1 g/min.Malvern (dry powder) particle size measurement gave a d(50) of 1.2 μm.

Formulation 15: Formulation 14 was pre-blended in a pestle with aspatula with 5% micronised l-leucine. This blend was further micronisedwith an injector air pressure of 8 bar, grinding air pressure of 1.5 barand powder feed rate of ˜1 g/min. Malvern (dry powder) particle sizemeasurement gave a d(50) of 1.2 μm.

Formulation 16: The pure clomipramine hydrochloride was micronised withan injector air pressure of 7 bar, grinding air pressure of 5 bar andpowder feed rate of ˜10 g/min. Malvern (dry powder) particle sizemeasurement gave a d(50) of 1.0 μm.

Formulation 17: The pure clomipramine hydrochloride was micronised withan injector air pressure of 7 bar, grinding air pressure of 5 bar andpowder feed rate of ˜10 g/min. This micronised clomipraminehydrochloride was pre-blended in a pestle with a spatula with 5%micronised l-leucine. This blend was then micronised with an injectorair pressure of 7 bar, grinding air pressure of 5 bar and powder feedrate of ˜10 g/min. Malvern (dry powder) particle size measurement gave ad(50) of 0.95 μm.

Formulation 18: The pure clomipramine hydrochloride was pre-blended in apestle with a spatula with 5% magnesium stearate. This blend wasmicronised with an injector air pressure of 7 bar, grinding air pressureof 5 bar and powder feed rate of ˜10 g/min. Malvern (dry powder)particle size measurement gave a d(50) of 0.95 μm.

Formulation 19: The pure clomipramine hydrochloride was micronised withan injector air pressure of 7 bar, grinding air pressure of 1 bar andpowder feed rate of ˜1 g/min. Malvern (dry powder) particle sizemeasurement gave a d(50) of 1.8 μm.

This pre-micronised clomipramine hydrochloride was then blended in apestle with a spatula with 5% micronised l-leucine. This blend was thenmicronised with an injector air pressure of 7 bar, grinding air pressureof 1 bar and powder feed rate of ˜1 g/min. Malvern (dry powder) particlesize measurement gave a d(50) of 1.38 μm.

Formulation 20: The pure clomipramine hydrochloride was micronised withan injector air pressure of 7 bar, grinding air pressure of 1 bar andpowder feed rate of ˜10 g/min. Malvern (dry powder) particle sizemeasurement gave a d(50) of 3.5 μm.

This pre-micronised clomipramine hydrochloride was then blended in apestle with a spatula with 5% micronised l-leucine. This blend was thenmicronised with an injector air pressure of 7 bar, grinding air pressureof 1 bar and powder feed rate of ˜10 g/min. Malvern (dry powder)particle size measurement gave a d(50) of 2.0 μm.

Formulation 21: The pure clomipramine hydrochloride was micronised withan injector air pressure of 7 bar, grinding air pressure of 3 bar andpowder feed rate of ˜1 g/min. Malvern (dry powder) particle sizemeasurement gave a d(50) of 1.2 μm.

This pre-micronised clomipramine hydrochloride was then blended in apestle with a spatula with 5% micronised l-leucine. This blend was thenmicronised with an injector air pressure of 7 bar, grinding air pressureof 3 bar and powder feed rate of ˜1 g/min. Malvern (dry powder) particlesize measurement gave a d(50) of 0.99 μm.

Formulation 22 The pure clomipramine hydrochloride was micronised withan injector air pressure of 7 bar, grinding air pressure of 3 bar andpowder feed rate of ˜10 g/min. Malvern (dry powder) particle sizemeasurement gave a d(50) of 1.6 μm.

This pre-micronised clomipramine hydrochloride was then blended in apestle with a spatula with 5% micronised l-leucine. This blend was thenmicronised with an injector air pressure of 7 bar, grinding air pressureof 3 bar and powder feed rate of ˜10 g/min. Malvern (dry powder)particle size measurement gave a d(50) of 1.1 μm.

Formulation 23: The clomipramine hydrochloride was pre-blended in apestle with a spatula with 5% micronised l-leucine. This blend wasmicronised with an injector air pressure of 7 bar, grinding air pressureof 5 bar and powder feed rate of ˜10 g/min. Malvern (dry powder)particle size measurement gave a d(50) of 1.8 μm.

Formulation 24: The pure clomipramine hydrochloride was micronised withan injector air pressure of 7 bar, grinding air pressure of 5 bar andpowder feed rate of ˜10 g/min.

This pre-micronised clomipramine hydrochloride was then blended in apestle with a spatula with 5% magnesium stearate. This blend was thenmicronised with an injector air pressure of 7 bar, grinding air pressureof 1 bar and powder feed rate of ˜10 g/min. Malvern (dry powder)particle size measurement gave a d(50) of 1.38 μm.

Formulation 25: Formulation 24 was then processed in the HosokawaMechanoFusion Minikit with 1 mm compression gap for 10 minutes. Malvern(dry powder) particle size measurement gave a d(50) of 1.39 μm.

Particle Size Distributions

The Malvern particle size distributions show that clomipraminehydrochloride micronised very readily to small particle sizes. Forexample, Formulation 16 micronised to 1.0 μm with one pass at therelatively high grinding pressure of 5 bar and the higher powder feedrate of 10 g/min.

Reducing the grinding pressure, for example to 1 bar as with Formulation19 interim powder, resulted in larger particles (d(50) ˜1.8 μm).Intermediate grinding pressure (3 bar) gave an intermediate particlesize distribution (d(50) ˜1.2 μm as for Formulation 21 interim powder).

Similarly, increasing powder feed rate, for example from 1 to 10 g/min,resulted in larger particles, as can be seen by comparing d(50)s forFormulations 19 and 20.

The addition of an additive material, for example leucine as inFormulation 23, appeared to reduce the milling efficiency. However, thischange may have been caused by the concomitant improvement inflowability of the original drug powder leading to a small butsignificant increase in the powder feed rate into the mill. It wasobserved in other studies that milling efficiency was increasinglysensitive to this powder feed rate as it increased above 10 g/min.

It appeared possible from this series of examples to design the millingparameters to select a particular d(50). For example, a d(50) of ˜1.4could be obtained either by repeated low pressure milling and low feedrate (Formulation 19) or by a mix of higher and lower pressure millingat a higher feed rate (Formulation 25).

Aspirair Dispersion Performance

Approximately 2 mg of each formulation was then loaded and sealed into afoil blister. This was then fired from an Aspirair device into a NextGeneration Impactor with air flow set at 60 l/min. The performance dataare summarised in Tables 8, 9 and 10.

TABLE 8 MD ED FPD Formulation (mg) (mg) (mg) MMAD 14 1.64 1.19 1.05 1.53(pure drug, jet milled at 8/1.5 bar) 15 1.55 1.32 1.19 1.68 (5% leucine,jet-milled at 8/1.5 bar) 16 2.414 1.832 1.493 1.80 (pure drug,jet-milled at 7/5 bar) 17 2.120 1.624 1.474 1.52 (5% leucine, jet-milledat 7/5 bar) 18 1.737 1.519 1.390 1.44 (5% MgSt, jet-milled at 7/5 bar)19 2.031 1.839 1.550 1.90 (5% leucine, jet-milled at 7/1 bar) 20 1.8211.685 1.071 2.44 (5% leucine, jet-milled at 7/1 bar) 21 1.846 1.5231.437 1.61 (5% leucine, jet-milled at 7/3 bar) 22 2.213 1.940 1.733 1.72(5% leucine, jet-milled at 7/3 bar) 23 1.696 1.557 1.147 2.13 (5%leucine, single pass at 7/5 bar) 24 1.743 1.542 1.274 1.82 (5% MgSt,jet-milled at 7/5 bar & mechanofused) 25 1.677 1.570 1.351 1.72 (5%MgSt, jet-milled at 7/5 bar)

TABLE 9 FPF % FPF % FPF % FPF % Formulation (<5 μm) (<3 μm) (<2 μm) (<1μm) 14 88 83 65 21 (pure drug, jet milled at 8/1.5 bar) 15 90 82 60 17(5% leucine, jet-milled at 8/1.5 bar) 16 82 71 51 14 (pure drug,jet-milled at 7/5 bar) 17 91 85 68 21 (5% leucine, jet-milled at 7/5bar) 18 91 90 73 20 (5% MgSt, jet-milled at 7/5 bar) 19 84 74 48 10 (5%leucine, jet-milled at 7/1 bar) 20 64 46 28 6 (5% leucine, jet-milled at7/1 bar) 21 94 88 67 14 (5% leucine, jet-milled at 7/3 bar) 22 89 80 5614 (5% leucine, jet-milled at 7/3 bar) 23 74 57 37 9 (5% leucine, singlepass at 7/5 bar) 24 83 68 47 15 (5% MgSt, jet-milled at 7/5 bar &mechanofused) 25 86 74 53 21 (5% MgSt, jet-milled at 7/5 bar)

TABLE 10 Re- covery Throat Blister Device Formulation % % % % 14 82 8 126 (pure drug, jet milled at 8/1.5 bar) 15 81 7 0 15 (5% leucine,jet-milled at 8/1.5 bar) 16 121 10 3 21 (pure drug, jet-milled at 7/5bar) 17 106 5 1 23 (5% leucine, jet-milled at 7/5 bar) 18 91 6 0 12 (5%MgSt, jet-milled at 7/5 bar) 19 107 10.6 1.3 8.2 (5% leucine, jet-milledat 7/1 bar) 20 96 24 1.3 6.1 (5% leucine, jet-milled at 7/1 bar) 21 97 30.6 16.9 (5% leucine, jet-milled at 7/3 bar) 22 116 7 0.6 16.9 (5%leucine, jet-milled at 7/3 bar) 23 87 18 2 6 (5% leucine, single pass at7/5 bar) 24 92 14 1 10 (5% MgSt, jet-milled at 7/5 bar & mechanofused)25 87 10 1 6 (5% MgSt, jet-milled at 7/5 bar)

The device retention appeared high (above 20%) where pure drug was used,and especially increased with small particle sizes (especially 1 μm andbelow): for example Formulations 14 and 16 had high drug retention.Device retention was lower with use of magnesium stearate, for exampleas with Formulation 18 where device retention was 12% despite a d(50) of0.95 μm. Device retention was also reduced below 20% when leucine wasused in combination with a particle size above 1 μm, for example withFormulation 22.

Throat deposition was reduced proportionately as particle size wasreduced. High throat deposition (>20%) occurs with particle size d(50)>2μm: e.g. Formulation 20. Throat deposition of below 10% was seen forparticle sizes below 1 μm. The reduced inertial behaviour of the smallerparticles may well contribute to this observation. However, as notedabove, device retention tended to be greater for such small particles.

It is argued that as particle size was reduced, increased adhesivenessand cohesiveness results in increased device retention. Thisadhesiveness and cohesiveness and hence device retention can be reducedby addition of force control agents, attached to the drug particlesurface (or drug and excipient particle surfaces, as appropriate). Asargued previously for the apomorphine and clobozam examples, anddemonstrated by the video study, in Aspirair it is believed that a levelof adhesiveness and cohesiveness is desirable to prolong lifetime in thevortex, yielding a slower plume, but adhesiveness and cohesivenessshould not be so high as to result in high device retention.Consequently a balance of particle size, adhesiveness and cohesivenessis required to achieve an optimum performance in Aspirair. The examplescontained herein indicate how such a balance may be achieved. Thisbalance may require modifying for each particular different materialcharacteristic.

Single step co-milling with a force control agent appears effective insome examples such as Formulation 18. Multiple stage processing may bemore effective, for example, where the conditions are selected toachieve particularly desirable effects. For example, first stage highpressure milling of pure drug may be used to produce the required sizedistribution (i.e. ˜1.4 μm), and a second stage lower pressureco-milling used to mix in the force control agent, whereby better mixingis achieved without milling and with reduced segregation of componentsin the mill. Such is shown in Formulation 25, where a combination ofboth relatively low throat deposition and low device retention areachieved.

The results of jet milling heparin with an FCA are set out below.

TABLE 11 d FPD Formulation d (10) d (50) d (60) (90) <5 μm Jet milledheparin + leucine 0.85 3.4 4.2 8.8 20.4 (1x) Jet milled heparin +leucine 0.95 3.5 4.1 7.0 37.1 (2x) Jet milled heparin + leucine 1.1 2.83.3 5.5 41.0 (3x) Jet milled pure heparin (2x) 7.0

The combination of heparin and leucine (95:5) was air jet milled using aHosokawa Micron AS50 mill. The material was passed up to three timesthrough the mill. The powder was then filled into capsules at 20 mg, andthen fired from a Monohaler into a twin stage impinger to give aresulting FPF(MD). The powder was also analysed by Malvern particlesizer, and the results are summarised in the table. Pure heparin powderwas air jet milled with two passes and gave an FPF(MD) of only 7%.

The optimum amount of additive material will depend on the chemicalcomposition and other properties of the additive material and upon thenature of the active material and/or excipient material, if present. Ingeneral, the amount of additive material in the composite activeparticles will be not more than 60% by weight, based on the weight ofthe active material and any excipient material. However, it is thoughtthat for most additive materials the amount of additive material shouldbe in the range of 40% to 0.25%, preferably 30% to 0.5%, more preferably20% to 2%, based on the total weight of the additive material and theactive material being milled. In general, the amount of additivematerial is at least 0.01% by weight based on the weight of the activematerial.

Clearly, many different designs of jet mills exist and any of these maybe used in the present invention. For example, in addition to the AS50Spiral jet mill and the MC50 Hosakawa Micron used in the experimentsdiscussed above, one can also use other spiral jet mills, pancake jetmills or opposed fluid bed jet mills. The feed rate for the jet millswill depend on their size. Small spiral jet mills might use a feed rateof, for example, 1 to 2 g per minute, whilst industrial scale mills willhave a feed rate in the order of kilograms per hour.

The properties of the co-jet milled particles produced using the presentinvention may, to an extent, be tailored or adjusted by making changesto the jet milling apparatus. For example, the degree of particlecoating and particle size reduction may be adjusted by changing thenumber of jets which are used in the apparatus, and/or by adjustingtheir orientation, that is, the angles at which they are positioned.

1. A method for making composite active particles for use in apharmaceutical composition for pulmonary inhalation, the methodcomprising jet milling active particles in the presence of particles ofadditive material and, optionally, air or a compressible gas or fluid.2. A method as claimed in claim 1, wherein the additive materialcomprises an amino acid, a metal stearate or a phospholipid.
 3. A methodas claimed in claim 2, wherein the additive material comprises one ormore of leucine, isoleucine, lysine, valine, methionine, phenylalanine.4. A method as claimed in claim 3, wherein the additive materialcomprises leucine and preferably L-leucine.
 5. A method as claimed inclaim 2, wherein the additive material comprises magnesium stearate. 6.A method as claimed in claim 2, wherein the additive material compriseslecithin.
 7. A method as claimed in any one of the preceding claims,wherein the jet milling is carried out at an inlet pressure of between0.1 and 3 bar.
 8. A method as claimed in any one of claims 1-6, whereinthe jet milling is carried out at an inlet pressure of between 3 and 12bar.
 9. A method as claimed in any one of the preceding claims, whereinat least 90% by volume of the active particles are less than 20 μm indiameter prior to jet milling.
 10. A method as claimed in any one of thepreceding claims, wherein at least 90% by volume of the additiveparticles are less than 20 μm in diameter prior to jet milling.
 11. Amethod as claimed in any one of the preceding claims, wherein jetmilling is carried out at temperatures below room temperature.
 12. Amethod as claimed in claim 11, wherein jet milling is carried out at atemperature below 10° C. and preferably below 0° C.
 13. A method asclaimed in any one of the preceding claims, wherein carrier particlesare also jet milled with the active particles and the particles ofadditive material.
 14. A method as claimed in claim 13, wherein thecarrier particles have a particle size of at least 20 μm.
 15. A methodas claimed in claim 13, wherein the carrier particles have a particlesize of less than 30 μm, preferably less than 20 μm and more preferablyless than 10 μm.
 16. Composite active particles for use in apharmaceutical composition made using a method as claimed in any one ofthe preceding claims.
 17. Composite active particles as claimed in claim16, for pulmonary inhalation.
 18. Composite active particles as claimedin either of claims 16 and 17, wherein the additive material forms acoating on the surface of the additive particles.
 19. Composite activeparticles as claimed in claim 18, wherein the coating is a discontinuouscoating.
 20. Composite active particles as claimed in either of claims18 and 19, wherein the coating of additive material is not more than 1μm in thickness.
 21. Composite active particles as claimed in any one ofclaims 16-20, having an MMAD of not more than 10 μm.
 22. Compositeactive particles as claimed in claim 21, having an MMAD of not more than5 μm, not more than 3 μm, not more than 2 μm, or not more than 1 μm. 23.Composite active particles as claimed in any one of claims 16-22,wherein at least 90% by weight of the composite active particles have adiameter of not more than 10 μm.
 24. Composite active particles asclaimed in claim 23, wherein at least 90% by weight of the particleshave a diameter of not more than 5 μm, not more than 3 μm, or not morethan 1 μm.
 25. A pharmaceutical composition comprising composite activeparticles as claimed in any one of claims 16-24.
 26. A composition asclaimed in claim 25, wherein the composition is for pulmonaryinhalation.
 27. A composition as claimed in either of claims 25 and 26,wherein the composition is a dry powder composition.
 28. A compositionas claimed in claim 27, wherein the composition further comprisescarrier particles.
 29. A composition as claimed in any one of claims25-28, wherein the composition has a FPF(ED) of at least 70%.
 30. Acomposition as claimed in claim 29, wherein the FPF(ED) is at least 80%,at least 85%, or at least 90%.
 31. A composition as claimed in any oneof claims 25-28, wherein the composition has a FPF(MD) of at least 60%.32. A composition as claimed in claim 29, wherein the FPF(MD) is atleast 70%, at least 80%, or at least 85%.
 33. A dry powder inhalercontaining a composition as claimed in any one of claims 25-32.
 34. Useof an additive material as a milling aid in the jet milling of an activematerial.